(1R,2R,3S,5S)-(−)-cocaine (1), also known as benzoylmethylecgonine or methyl-(1R,2R,3S,5S)-3-(benzoyloxy)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate (hereafter referred to as “cocaine”), is a crystalline tropane alkaloid obtained from the leaves of the coca plant. (1R,2R,3S,5S)-(−)-cocaine is the only stereoisomer of this molecule that is addictive (Carrol et al., 1991, J. Med. Chem. 31:883-886).

Cocaine is a stimulant of the central nervous system and an appetite suppressant. Specifically, it is a serotonin-norepinephrine-dopamine reuptake inhibitor (SNDRI)—also referred to as a triple reuptake inhibitor (TRI)—acting as an exogenous catecholamine transporter ligand. As a SNDRI/TRI, cocaine acts simultaneously as a reuptake inhibitor for the monoamine neurotransmitters—serotonin, norepinephrine (noradrenaline) and dopamine—by blocking the action of the serotonin transporter (SERT), norepinephrine transporter (NET) and dopamine transporter (DAT), respectively. This, in turn, leads to increased extracellular concentrations of these neurotransmitters and an increase in serotonergic, noradrenergic or adrenergic, and dopaminergic neurotransmission.
The pharmacodynamics of cocaine involves various neurotransmitter systems. The most extensively studied effect of cocaine on the central nervous system is the blockade of the dopamine transporter protein. Dopamine transmitter released during neural signaling is normally recycled via the transporter—the transporter binds dopamine and pumps it out of extracellular space back into the presynaptic neuron, where it is taken up into storage vesicles. There is a great deal of evidence that dopamine transmission is volume transmission. DATs are mostly extrasynaptic, and dopamine is cleared from the synapse by diffusion (Rice & Cragg, 2008, Brain. Res. Rev. 58:303-13). Cocaine binds tightly at the dopamine transporter, forming a complex that blocks the transporter's function. The dopamine transporter can no longer perform its reuptake function, and thus dopamine accumulates outside dopamine cells. This results in an enhanced and prolonged post-synaptic effect of dopaminergic signaling at dopamine receptors on the receiving neuron. Prolonged exposure to cocaine, as derived from habitual use, leads to homeostatic dysregulation of normal (i.e. without cocaine) dopaminergic signaling via down-regulation of dopamine receptors and enhanced signal transduction. The decreased dopaminergic signaling after chronic cocaine use may contribute to depressive mood disorders and sensitize this important brain reward circuit to the reinforcing effects of cocaine (e.g. enhanced dopaminergic signaling only when cocaine is self-administered). This sensitization contributes to the intractable nature of addiction and relapse.
Cocaine has also been shown to directly stabilize the dopamine transporter on the open outward-facing conformation, whereas other stimulants (such as phenethylamines) stabilize the closed conformation. Further, cocaine binds in such a way to the dopamine transporter as to inhibit a hydrogen bond innate to transporter, whereas binding of amphetamine and similar molecules to the dopamine receptor does not inhibit formation of such bond (Kniazeff et al., 2008, Nature Neuroscience 11(7):780).
Cocaine binding affects multiple serotonin (5-hydroxytryptamine, or 5-HT) receptors, and inhibition of the re-uptake of 5-HT is thought to be an important contributor to the effects of cocaine (Carta et al., 2003, Eur. J. Pharmacol. 459(2-3):167-69). The 5-HT2 receptor (particularly the subtypes 5-HT2AR, 5-HT2BR and 5-HT2CR) show influence in the evocation of hyperactivity displayed in cocaine use (Filip et al., 2004, J. Pharmacol. Exp. Ther. 310(3):1246-54).
Cocaine functions as a sigma ligand agonist, and examples of sigma receptors affected are NMDA and the D1 dopamine receptor (Liuch et al., 2005, Pharmacol. Biochem. Behav. 82(3):478-87). Cocaine also blocks sodium channels, thereby interfering with the propagation of action potentials. Because of this effect, cocaine, similarly to lignocaine and novocaine, acts as a local anesthetic. Cocaine has some target binding to the site of the kappa-opioid receptor as well, and enhances dopaminergic transmission from the substantia nigra.
Cocaine is thus a highly potent bioactive molecule, acting in various receptor and reward systems. Because of the way it affects the mesolimbic reward pathway, cocaine is highly addictive. Cocaine abuse and addiction is now a worldwide problem, and approximately 4.5 million people in the United States are thought to be chronic abusers of this drug. The cocaine market in the United States has been estimated to exceed $35 billion and has an enormous impact socio-economically. Unfortunately, there are no medications currently available for the treatment of cocaine addiction.
A compound that acts as an antagonist or agonist of cocaine in its binding to various receptors could in principle be used in the treatment of cocaine addiction, as long as it is not addictive or cause the same degree of euphoria in individuals. In another aspect, such compound could be used as an anesthetic agent, mimicking the anesthesia provided by cocaine without its well-known addictive properties.
A starting point for the identification of a cocaine analog could be the preparation and characterization of compounds that share the general structure of the natural product. The synthetic efforts targeting cocaine analogs has been concentrated on partially degrading cocaine itself and derivatizing the resulting scaffold to obtain novel tropane analogs. For example, the ester groups at the C-2 and C-3 centers of cocaine may be hydrolyzed, or the N-8 center of cocaine may be demethylated, and the corresponding compound may then be derivatized using standard chemical procedures.
However, systematic exploration of structure-activity relationships (SAR) around the cocaine molecule is currently hampered by the lack of a synthetic methodology that allows one to introduce substituents in the cocaine-tropane skeleton in a regiospecific and stereospecific manner. In one aspect, it is challenging to stereospecifically prepare a cocaine analog with C-2 and C-3 substituents in the cis orientation, an arrangement that is thought to be necessary for bioactivity. For example, Tufariello and coworkers disclosed a non-stereoselective synthesis of racemic cocaine (J. Am. Chem. Soc. 1978, 101:2435-2442). This synthesis comprised a nitrone intermediate, which the authors could not prepare as a pure enantiomer, and therefore this methodology did not allow the development of an asymmetric synthesis of cocaine.
In another aspect, the synthetic approaches disclosed so far do not allow the introduction of substituents at the C-1 and C-4 positions of the cocaine-tropane skeleton (Singh, 2000, Chem. Rev. 100, 925-1024). These synthetic limitations must be overcome to open the way to the synthesis and biological characterization of cocaine analogs with diverse substitutions at those positions.
There is thus a need for the identification and characterization of novel cocaine analogs. These analogs may be useful in understanding the biological activities of cocaine. These analogs may have novel receptor selectivities and find use as pharmaceutical tools in the treatment of drug addiction. These analogs may find further use as inhibitors of reuptake of one or more monoamine neurotransmitters. These analogs may also find use as non-addictive anesthetic agents. Currently there is no synthetic method that allows the chiral synthesis of cocaine analogs wherein substitution may be systematically and stereoselectively introduced at the C-1, C-2, C-3, C-4 and N-8 positions. Such synthetic method would allow the exploration of the chemical diversity around the cocaine scaffold and the preparation of novel cocaine analogs that are not synthetically accessible currently. The present invention addresses and meets these needs.